The Buck Institute for Research on Aging, Novato, CA 94945, USA.
Cell Stem Cell. 2012 Aug 3;11(2):253-63. doi: 10.1016/j.stem.2012.04.026. Epub 2012 Jun 28.
Huntington's disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by the replacement of the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32-positive neurons in vitro and in vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-β, BDNF, and caspase activation) and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy.
亨廷顿病（HD）是由亨廷顿基因中的 CAG 扩展引起的。亨廷顿蛋白中的多聚谷氨酰胺链的扩展导致 HD 患者纹状体中的大量细胞死亡。我们报告说，使用同源重组，可以将源自 HD 患者成纤维细胞的人诱导多能干细胞（iPSC）中扩展的 CAG 重复序列替换为正常重复序列，并且该校正在 iPSC 分化为体外和体内的 DARPP-32 阳性神经元中持续存在。此外，HD-iPSC 的校正使致病性 HD 信号通路（钙粘蛋白、TGF-β、BDNF 和半胱天冬酶激活）正常化，并逆转了疾病表型，例如神经干细胞对细胞死亡的易感性和改变的线粒体生物能量学。能够从 HD 患者中获得患者特异性、基因校正的 iPSC 将为相同遗传背景下提供相关疾病模型，并且是最终将这些细胞用于细胞替代治疗的关键步骤。
